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Ann Thorac Surg 2004;78:1650-1657
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Glucose-Insulin-Potassium in Cardiac Surgery: A Meta-Analysis

Wolfgang Bothe, MDa, Manfred Olschewski, MSb, Friedhelm Beyersdorf, MDa, Torsten Doenst, MDa,*

a Department of Cardiovascular Surgery Freiburg, Germany
b Department of Medical Biometry and Statistics, University of Freiburg, Freiburg, Germany

Accepted for publication December 29, 2003.

* Address reprint requests to Dr Doenst, Department of Cardiovascular Surgery, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany
doenst{at}ch11.ukl.uni-freiburg.de


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 
BACKGROUND: Glucose-insulin-potassium therapy (GIK) has been suggested to reduce mortality and improve postoperative recovery after cardiac surgery. We performed a meta-analysis of all randomized studies using GIK in cardiac surgery.

METHODS: A systematic Medline search for all GIK studies in cardiac surgery was carried out. Randomized studies investigating the recovery of contractile function as a primary endpoint were included in the meta-analysis.

RESULTS: Thirty-five GIK trials were identified. Twenty-four studies were excluded because of lack of randomization, supplementary administration of other substances, or due to other primary endpoints. Eleven studies were included with a total of 468 patients who underwent either coronary artery bypass grafting or heart valve replacement. Six studies noted a significant improvement in postoperative recovery. One study demonstrated no effect. In four studies, no comparable statistical analysis was available. GIK patients required similar or lesser doses of catecholamines. From the available data we estimated a weighted mean of relative improvement in postoperative recovery of cardiac index for GIK patients versus controls of 11.4%. Five of 11 studies reported the incidence of postoperative atrial fibrillation (AF). AF occurred in 23% (20/86) in GIK versus 42% (36/86) in control patients (p = 0.009).

CONCLUSIONS: The findings indicate that GIK may considerably improve postoperative recovery of contractile function and reduce the incidence of atrial arrhythmias after cardiac surgery. However, several factors limit the power of this analysis and large, randomized multicenter trials are needed to fully assess the efficacy of GIK after cardiac surgery.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 
Since the first combined application of glucose, insulin, and potassium (GIK) in 1962 [1], GIK has been widely applied under various experimental and clinical conditions [2]. In acute myocardial infarction (AMI), GIK has been demonstrated to reduce morbidity and mortality [3–5]. A recent meta-analysis that involved nine clinical trials with 1932 patients calculated that GIK reduced in-hospital mortality in patients with AMI by 28% [4]. However, all but one of the studies cited in this meta-analysis were performed without thrombolytic therapy and the benefit of GIK in addition to thrombolysis was questioned. Contrary to expectations, a multicenter trial by a Latin American collaborative group [5] and a controlled randomized trial in diabetic patients with AMI [3] applying both thrombolytic therapy and GIK repeated these results and thereby demonstrated that GIK also has its place in contemporary practice.

In cardiac surgery, GIK has been applied in several studies suggesting similar effects, ie, a reduction in mortality and improvement of postoperative recovery [6–11]. However, the results of these studies were also questioned due to the low number of patients recruited, inadequate study design, differences in protocols and inclusion criteria, as well as a lack of randomization. Finally, the time point of GIK application and the primary endpoints assessed are other factors with conceivable influence on outcome. Because recovery of function is one of the most important postoperative aspects, we conducted a meta-analysis of all randomized GIK studies in cardiac surgery that used recovery of contractile function as a primary endpoint.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Conclusion
 Acknowledgments
 References
 
Search Strategy
A systematic Medline search was performed using the search terms "cardiac surgery" and "heart surgery" and a set of terms for GIK: glucose, insulin, glucose-insulin, and glucose-insulin-potassium (GIK). We supplemented electronic searches by fact checking the reference lists provided by the studies selected and review articles on GIK therapy.

Inclusion and Exclusion Criteria
We included all randomized GIK studies in cardiac surgery that investigated the recovery of contractile function as a primary endpoint. We considered trials published in the English language. Nonrandomized studies, studies with other primary endpoints, or studies that administered other substances in addition to GIK were excluded.

Statistical Analysis
Data are presented as mean ± standard deviation for quantitative variables and as absolute and relative frequencies for qualitative variables. Because we had no access to the individual patient data from the trials, we had to restrict our analyses to combining the results presented in the corresponding original manuscripts. To estimate the GIK overall effect on postoperative recovery of cardiac index, we used the weighted sum of percentage differences of GIK patients versus placebo from all available trials. The overall rates of postoperative AF were estimated within the treatment groups by pooled weighted averages over all trials. The effect of GIK on preventing AF was tested by the Mantel-Haenszel statistic; p less than 0.05 was used as the level of significance.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Conclusion
 Acknowledgments
 References
 
A total of 35 trials, conducted between 1970 and 2002, were identified [6–40]. Twenty-four studies were excluded [8–10, 20–40]. Three studies were excluded because of lack of randomization [8, 10, 21], 1 because the data were collected retrospectively [32], 1 because aspartate and glutamate were administered supplementary to GIK [31], 2 because there was no comparison to an adequate control group [20, 40], 1 because GIK patients were treated by a cardiopulmonary bypass protocol that differed from that in the control group [33], and 16 because recovery of contractile function was not an endpoint [9, 22–30, 34–39]. Table 1 presents a list of the 24 studies excluded from the analysis, including the number of patients in each study, the number of deaths reported, and the reason for exclusion from the analysis. These studies comprise a total of 3577 patients (1464 control group and 2113 GIK treated patients). A total of 57 patients (4.9%) died in the control group and 39 (2.1%) of the GIK-treated patients died. The exact reason for death was not given in each case. The latest and largest randomized trial [38] demonstrated no benefit on myocardial infarction and low output syndrome when insulin was added into the cardioplegic solution in low concentrations.


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  		Table 1. Studies That Were Excluded From the Analysis

 
Table 2 demonstrates the design characteristics of all trials included in the meta-analysis. Eleven studies were identified that were all randomized and had variables for the assessment of recovery of function as primary endpoints (cardiac index, dp/dtmax, ejection fraction [EF]) [6, 7, 11–19]. Those 11 studies included a total of 468 patients (229 control group and 239 GIK-treated patients) who underwent either CABG or heart valve replacement. Inclusion and exclusion criteria differed greatly among the groups. Whereas some studies had diabetes mellitus as exclusion criteria [7, 16, 18], others included only diabetic patients [19]. Similarly, some studies included patients with preserved ventricular function [13, 14, 16, 19], although others also included patients with impaired ventricular function [11, 12, 15, 17]. Two of the studies included reported mortality. Brodin and colleagues [15] lost 2 patients treated with GIK. One patient died 31 days postoperatively due to complications of cerebral emboli from a calcified aortic wall, and the other patient died of a hemolytic disorder after 33 days. Besogul and coworkers [17] reported one late death in each group. One was caused by postoperative renal failure and the other was the consequence of septic shock.


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  		Table 2. Design Characteristics of the Studies Included

 
Table 3 illustrates the GIK regimens of the 11 studies analyzed. The protocols differed greatly. In one study, GIK was administered preoperatively [17], in five studies perioperatively [11, 13–15, 18]. In two studies GIK was given postoperatively [12, 19] and in three studies GIK was applied perioperatively as well as postoperatively [6, 7, 16]. The duration of GIK treatment ranged from a few seconds (given as bolus at the end of the operation [12]) to approximately 18 hours (applied perioperatively as well as postoperatively [16]). The total amounts of glucose, insulin, and potassium given differed by a factor greater than 100 among studies.


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  		Table 3. GIK Regimens of the Studies Analyzed

 
In 8 of 11 studies it was possible to compare preoperative versus postoperative hemodynamic measurements [6, 7, 11, 13–16, 18]. Of these 8 studies, 1 study used dp/dtmax [13], 1 study used EF [15], and 6 studies used cardiac index [6, 7, 11, 14, 16, 18] as a parameter of functional recovery. Figure 1 illustrates the differences of the preoperative versus the postoperative cardiac indices ({Delta}CI) in those 6 studies. Except for 1 study, GIK patients manifested either a lesser reduction or a greater improvement in cardiac index after surgery compared with controls.



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  		Fig 1. Differences between preoperative and postoperative cardiac index of the control groups and groups receiving GIK in six studies where preoperative and postoperative measurements of cardiac index were obtained. (GlK = glucose-insulin-potassium infusion.)

 
Table 4 indicates the hemodynamic variables of all 11 studies included and the results from the preoperative and postoperative hemodynamic measurements. For better comparison we used the first preoperative measurements and the postoperative measurements closest to the time point of 4 hours postoperatively from these studies. These postoperative time points ranged from 0 to 6 hours after the operation. The comparisons revealed a significantly better postoperative recovery of contractile function in the GIK patients compared to control patients in seven studies [6, 7, 11, 13–15, 19]. Three studies reported no benefit of GIK [12, 16, 17]. However, Besogul and coworkers [17] noted a significant increase of cardiac index 12 hours and 24 hours postoperatively in the GIK treated patients, and Svensson and associates [12] noted a significant increase in cardiac index in patients 10, 20, and 30 minutes after receiving a bolus dose of 7.5 IU/kg of insulin. In one study, no statistical analysis was available [18].


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  		Table 4. Results From Preoperative and Postoperative Hemodynamic Measurements of the Studies Included

 
In 9 of 11 studies included it was possible to obtain information on the postoperative application of catecholamines. Five of the studies revealed similar, and four of the studies lower inotropic requirements in the GIK group (as indicated by an index ≥ 1 in Table 4). Five of 11 studies commented on the use of postoperative intraaortic balloon pump support, but did not demonstrate any significant difference between the groups [7, 13, 14, 16, 17].

In an attempt to estimate the overall impact of GIK on postoperative recovery of cardiac function as compared to controls, we calculated within each study the relative differences in preoperative cardiac index versus postoperative values for each group. We then calculated the percentage differences between the control and the GIK groups in each study and calculated weighted sums of these values with weights according to the number of cases in each study. This calculation revealed a mean of 11.4% improvement of recovery of cardiac index by GIK during the postoperative course. Because it was impossible to quantitate the impact of dp/dtmax or EF on cardiac index, we did not include the studies of Lolley [13] and Brodin and colleagues [15] in these calculations. However, if those studies had been included in our comprehensive analysis, the relative improvement in postoperative recovery would be slightly decreased by the study reported by Brodin and colleagues (to 11.2%), and dramatically increased by the study reported by Lolley (to 26.0%). Becasuse we had no access to the individual patient data, it was not possible to perform a test whether this improvement for GIK is statistically significant. However, judging the reported p values from the different studies a significant difference seems likely.

Despite low patient numbers we performed subanalyses of the studies with different application time points. If the weighted difference is calculated for those studies using GIK perioperatively [11, 13–15, 18], the value is 6.1%. In those studies applying GIK perioperatively as well as postoperatively [6, 7, 16], the relative improvement by GIK is 19.5%.

Six of 11 studies analyzed included patients with diabetes mellitus [6, 11, 13, 15, 17, 19]. Three of those 6 trials provided information on blood glucose levels during GIK therapy [6, 11, 19]. Two studies reported significant hyperglycemia during GIK therapy [11, 19]. In one study, GIK resulted in an improvement in glycemic control [6]. All studies reporting blood glucose levels in patients without diabetes mellitus demonstrated the presence of hyperglycemia [7, 14, 16]. All 6 trials that included patients with diabetes reported a significant improvement in postoperative contractile function.

Five of the trials analyzed reported the incidence of postoperative atrial fibrillation with a total of 172 patients [6, 7, 14, 16, 17]. Table 5 demonstrates the incidences of postoperative atrial fibrillation in each of those studies. Three of 5 studies had less atrial fibrillation in the GIK than in the control groups [6, 7, 17]. The two studies by Wistbacka and coworkers [14, 16] had a low incidence of atrial fibrillation and did not demonstrate any difference between GIK and control patients. In an attempt to assess the overall impact of GIK on postoperative AF, we estimated the overall rates of postoperative AF for all studies within the treatment groups by pooled weighted averages, and tested them by a Mantel-Haenszel statistic. The test revealed a significantly lower incidence of postoperative AF in GIK-treated patients (p = 0.009).


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  		Table 5. Incidence of Postoperative AF With and Without GIK

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Conclusion
 Acknowledgments
 References
 
We demonstrate in this analysis that GIK has the potential to considerably improve recovery of contractile function in patients after cardiac surgery. GIK is further effective in reducing the incidence of postoperative atrial fibrillation.

The first use of GIK in cardiac surgery was described in 1969. Braimbridge and associates [41] reported that GIK was successfully used to treat patients with low cardiac output not responding to isoprenaline, digoxin or pacemaking after triple-valve replacement. While it appears unrealistic to expect such dramatic effects of GIK in the present day postoperative care of cardiac surgical patients, it is presumable that GIK may still have a considerable impact on recovery of contractile function. We calculated an 11.4% improvement in recovery of cardiac index throughout the studies analyzed. In analogy, Fath-Ordoubadi and colleagues [4] present a 28% reduction in mortality in their meta-analysis of GIK for the treatment of myocardial infarction. It is conceivable that the apparently better efficacy of GIK in the treatment of myocardial infarction is due to the heterogeneity of the studies in our analysis. If this were the case, our calculated 11.4% improvement in recovery of cardiac index should consist of some studies with great and some with lesser benefit. This consideration shifts the focus to the timing of GIK application. Our subanalyses revealed greater relative improvement by GIK when the calculations were limited to the studies using GIK perioperatively as well as postoperatively (19.5% vs 11.4%) [6, 7, 16]. As the patient number may be too low to allow firm judgements, the therapeutic potential of GIK administration early after ischemia is supported by experimental studies in pigs and rats, reporting a direct, nonmetabolic effect of insulin on postischemic contractile function [42] and a reduction in infarct size during reperfusion [43, 44].

It is indirectly also supported by the largest randomized trial in this area, the Insulin Cardioplegia Trial, which did not demonstrate a benefit of insulin during cardioplegia [38]. This observation was surprising because the same investigators had demonstrated benefits of the same protocol before [18]. However, the endpoints of the studies differed. While in the earlier study cardiac index was used as an endpoint, the larger trial used myocardial infarction and the presence of low output syndrome as endpoints. It has been questioned whether these are the only important aspects to assess with respect to recovery of patients after cardiac surgery [45]. The potential efficacy of insulin given during cold cardioplegia may also be challenged, because substrate metabolism should be minimal. Based on these observations and the results of this meta-analysis it appears most reasonable at this time to apply GIK or insulin as early after reperfusion as possible. With regard to the data available, it is currently difficult to make a recommendation on the best duration of insulin treatment. Although prolonged administration of insulin may reduce morbidity and mortality in patients requiring longer intensive care unit stays [46, 47], it may interfere with patient transfer in those recovering uneventfully. However, these questions can only be fully resolved when tested by large, randomized trials and when the underlying mechanisms are discovered.

Although GIK was initially used as a polarizing agent to promote electrical stability [1, 48], the mechanistic focus shifted over the years towards GIK-induced changes in metabolism [23, 24, 26, 49, 50]. Mainly three metabolic effects of GIK have been attributed to cause beneficial effects in cardiac surgery: First preischemic application of insulin may improve ischemia tolerance by increasing glycogen content. The reduction of free fatty acid levels in plasma by insulin has been another metabolic effect and the direct activation of glucose oxidation and utilization has been the third. Other mechanisms discussed have been an increase in the activation of sympathetic nerves, a vasodilatation by insulin and, consequently, a decrease in peripheral vascular resistance. Finally, insulin has been revealed to activate plasminogen activator inhibitor 1, the significance of which with respect to GIK is still unclear (see Doenst and coworkers [2] for detailed review).

Six trials included patients with diabetes. They all reported significantly better postoperative contractile function in the GIK group [6, 11, 13, 15, 17, 19] independent from hyperglycemia [11, 19]. Contrary to expectations, one could conclude that GIK therapy is of particular benefit to diabetic patients. One could also conclude that blood glucose levels after surgery have no impact on the effect of GIK on the recovery of contractile function. Finally, there is ample evidence that strictly controlled blood glucose levels reduce morbidity and mortality in patients undergoing cardiac operations [46, 47] independent of the presence or absence of diabetes mellitus. Thus, it seems most plausible to apply GIK or insulin without causing hyperglycemia.

It is also unclear how the effect of GIK on AF is mediated. There is similar heterogeneity with respect to the timing of GIK application as with the effects on cardiac index. However, there is evidence that insulin cardioplegia is not effective in reducing postoperative AF [35]. Recent evidence suggests an effect of insulin on the cardiac membrane potential through a newly described ion channel [51]. This influence may lead to a "membrane stabilizing" effect and could explain its reducing effects on AF. It appears therefore reasonable to conclude that the effects of GIK or insulin on recovery of contractile function and the rate of AF are best exploited by an administration early after ischemia.

The beneficial effects of GIK in cardiac surgery are presented here by way of a meta-analysis. As pointed out by others [52, 53], meta-analyses are associated with certain limitations. First, the size of the data pooled is important, because the results become more reliable as size increases. The number of 468 patients included in our analysis is low and may not be large enough for a valid statement. Second, trials with negative results are less likely to be published and studies not observing effects on contractile function may not present the data with contractile function as primary endpoint. This publication bias may lead to an overestimation of the true difference between the groups. A third factor is the heterogeneity among the studies analyzed. This heterogeneity includes the presence or absence of diabetes mellitus, the time point or duration of GIK application as well as ventricular function before surgery (see Tables 2 and 3). Fourth, cardiac index is a load sensitive parameter and may vary based on the volume status of the patients. Unfortunately, it was impossible for us to account for this influence because most studies did not provide information on preload and afterload. Finally, the GIK studies included were performed between 1984 and 2001. The surgical treatment of cardiac patients has changed over the years and the results from older studies may not be transferrable to contemporary practice. Irrespective of these limitations, the potential benefit that may be derived from this metabolic therapy is worth further investigating.


   Conclusion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Conclusion
Acknowledgments
 References
 
We demonstrate in this analysis that GIK may considerably improve recovery of contractile function in patients after cardiac surgery. GIK may further be effective in reducing the incidence of postoperative atrial fibrillation. However, several factors limit the power of this analysis and large, randomized multicenter trials are required to fully assess the efficacy of GIK in cardiac surgery.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Conclusion
 Acknowledgments
References
 
TD was supported by the Emmy Noether-Program of the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, Do602/2). We wish to thank Dr Richard D. Weisel for helpful comments and suggestions.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 

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